Two distinct congenital arrhythmias evoked by a multidysfunctional Na+ channel

Citation
Mw. Veldkamp et al., Two distinct congenital arrhythmias evoked by a multidysfunctional Na+ channel, CIRCUL RES, 86(9), 2000, pp. E91-E97
Citations number
30
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
CIRCULATION RESEARCH
ISSN journal
00097330 → ACNP
Volume
86
Issue
9
Year of publication
2000
Pages
E91 - E97
Database
ISI
SICI code
0009-7330(20000512)86:9<E91:TDCAEB>2.0.ZU;2-2
Abstract
The congenital long-QT syndrome (LQT3) and the Brugada syndrome are distinc t, life-threatening rhythm disorder; linked to autosomal dominant mutations in SCN5A, the gene encoding the human cardiac Na+ channel. It is believed that these two syndromes result from opposite molecular effects: LQT3 mutat ions induce a gain of function, whereas Brugada syndrome mutations reduce N a+ channel function, Paradoxically, an inherited C-terminal SCN5A mutation causes affected individuals to manifest electrocardiographic features of bo th syndromes: QT-interval prolongation (LQT3) at slow heart rates and disti nctive ST-segment elevations (Brugada syndrome) with exercise. In the prese nt study, we show that the insertion of the amino acid 1795insD has opposit e effects on two distinct kinetic components of Na+ channel gating (fast an d slow inactivation) that render unique, simultaneous effects on cardiac ex citability. The mutation disrupts fast inactivation, causing sustained Nacurrent throughout the action potential plateau and prolonging cardiac repo larization at slow heart rates, At the same time, 1795insD augments slow in activation, delaying recovery of Na+ channel availability between stimuli a nd reducing the Na+ current at rapid heart rates, Our findings reveal a nov el molecular mechanism for the Brugada syndrome and identify a new dual mec hanism whereby single SCN5A mutations may evoke multiple cardiac arrhythmia syndromes by influencing diverse components of Na+ channel gating function . The full text of this article is available at http://www.circresaha.org.